A dacomitinib intermediate and dacomitinib and a preparation method thereof

Abstract

A dacomitinib intermediate and dacomitinib and a preparation method thereof, belonging to the technical field of pharmaceutical chemistry. The preparation method of dacomitinib is to use p-methoxybenzaldehyde as a raw material, react with hydroxylamine, and then nitrate, reduce, acylate, and nitrate again to obtain N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide. Then, after reduction, condensation, ring closure, and alkaline hydrolysis, N 4 ‑(3‑chloro‑4‑fluorophenyl)‑7‑methoxyquinazoline‑4,6‑diamine, (E)‑4‑(piperidin‑1‑yl)‑2‑butenoyl chloride and an acid binding agent to obtain dacomitinib. 4 In the process of preparing ‑(3‑chloro‑4‑fluorophenyl)‑7‑methoxyquinazoline‑4,6‑diamine, the ring-closure reaction and the introduction of the fluorochloroaniline fragment are carried out in the same step, avoiding the use of highly polluting halogenating reagents. This is an efficient and environmentally friendly synthetic route suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and more specifically, relates to a dacomitinib intermediate and dacomitinib and a preparation method thereof. Background Art

[0002] Dacomitinib is an oral, highly effective, targeted quinolone small molecule inhibitor developed by Pfizer. It can inhibit the activity of multiple EGFR-TKs (EGFR / HER1, HER2 and HER4). It achieves irreversible inhibition by covalently binding to cysteine ​​residues in the catalytic domain of the HER receptor, and also activates downstream signal transduction pathways such as Ras-Raf-MAPK, PLCgamma-PKC-NFkB and PI3K / AKT through phosphorylation driven by the carboxyl-terminal tyrosine kinase, playing a role in tumor growth, metastasis and treatment resistance.

[0003] The chemical name of dacomitinib is (E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]-4-(piperidin-1-yl)-2-butenamide, and its structural formula is:

[0004]

[0005] At present, the preparation method of dacomitinib includes the dacomitinib synthesis method reported in its original research patent US2005250761A1: 3-chloro-4-fluoroaniline and 3,4-dimethoxybenzaldehyde are subjected to reductive amination to obtain the intermediate 3-chloro-N-(3,4-dimethoxybenzyl)-4-fluoroaniline; 2-amino-4-fluorobenzoic acid is subjected to cyclization, nitration, chlorination, and then condensation, substitution, reduction, acylation, and deprotection with 3-chloro-N-(3,4-dimethoxybenzyl)-4-fluoroaniline to obtain the target dacomitinib, with a total yield of 31.5%. This method has a long route, a low total yield, and a high cost. The amino protection and deprotection reactions are incomplete, and new impurities are easily generated, which is not suitable for industrial large-scale production.

[0006] The process route of the original patent US2005250761A1 is as follows:

[0007]

[0008] Patent CN113045504A discloses a method for preparing dacomitinib, which uses 3-amino-4-methoxybenzyl ester as a raw material, and obtains dacomitinib through condensation, nitration, reduction, cyclization, halogenation, and coupling, with a total yield of 57.1%. Compared with the original research route, the yield is improved, but thionyl chloride is used as a halogenation reagent, which is highly toxic.

[0009]

[0010] Patent CN113024472A discloses a method for preparing dacomitinib, a lung cancer targeted drug, using 3-amino-4-methoxybenzonitrile as a raw material through condensation, nitration, hydrolysis, reduction, cyclization, halogenation, and coupling to obtain dacomitinib. The total yield of the route is 46.7%, but phosphorus oxychloride is used as a chlorination reagent, which causes great environmental pollution.

[0011]

[0012] Patent CN113004212A discloses a method for preparing dacomitinib, which uses 3-amino-4-methoxybenzonitrile as a raw material and 4-(piperidin-1-yl)but-2-enoyl chloride for condensation reaction, followed by nitration, reduction, condensation, and cyclization to obtain dacomitinib. The total yield of the route is 50.5%, which is higher than that of the original research route, but the yield of nitro reduction is low and the operation is complicated.

[0013]

[0014] Currently, the intermediate for synthesizing dacomitinib is mainly P05-3A, which has incomplete reaction, many impurities, low yield and high cost, which is not conducive to industrial promotion. Summary of the invention

[0015] The present invention aims to provide a method for preparing dacomitinib and an intermediate thereof which is environmentally friendly, low in cost, simple in operation and suitable for industrial production. Specifically, a dacomitinib intermediate and dacomitinib and a preparation method thereof are provided. The main raw materials involved are p-methoxybenzaldehyde, (E)-4-bromo-2-butenoic acid methyl ester, N,N-dimethylformamide dimethyl acetal (DMF-DMA), 3-chloro-4-fluoroaniline and piperidine, which are all cheap and readily available starting raw materials. The reaction conditions of each step are mild, and the intermediates and the final products are easy to purify and store. In the preparation process, the ring-closing reaction and the introduction of the fluorochloroaniline fragment are carried out in the same step, so that the use of highly polluting halogenated reagents is avoided. The present invention is an efficient and environmentally friendly synthesis route suitable for industrial production.

[0016] The present invention is achieved through the following technical solutions:

[0017] A dacomitinib intermediate of the present invention is N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide, and its structural formula is:

[0018]

[0019] The invention discloses a method for preparing a dacomitinib intermediate, comprising taking p-methoxybenzaldehyde as a raw material, reacting it with hydroxylamine, and then nitrating, reducing, acylating, and nitrifying again to obtain a dacomitinib intermediate, namely N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide.

[0020] The preparation method of N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide specifically comprises the following steps:

[0021] Step (1): mixing p-methoxybenzaldehyde ② with hydroxylamine to react and prepare p-methoxybenzonitrile ③;

[0022] Step (2): mixing p-methoxybenzonitrile ③ and a nitrating agent to carry out a nitration reaction to generate 3-nitro-4-methoxybenzonitrile ④;

[0023] Step (3): subjecting 3-nitro-4-methoxybenzonitrile ④ to a reduction reaction with a reducing agent to obtain 3-amino-4-methoxybenzonitrile ⑤;

[0024] Step (4): reacting 3-amino-4-methoxybenzonitrile ⑤ with an acylating agent to generate N-(5-cyano-2-methoxyphenyl)acetamide ⑥;

[0025] Step (5): reacting N-(5-cyano-2-methoxyphenyl)acetamide ⑥ with a nitrating agent to generate N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide ⑦.

[0026] In the step (1), the molar ratio of p-anisaldehyde②:hydroxylamine is 1:(1-5), more preferably 1:(1.1-1.3).

[0027] In the step (1), the reaction of p-methoxybenzaldehyde② and hydroxylamine is carried out in a solvent system, and the solvent used is preferably one or more of methanol, ethanol, water, dichloromethane, tetrahydrofuran, benzene, toluene, formic acid, acetic acid, and acetonitrile, and formic acid is more preferred. By volume ratio, p-methoxybenzaldehyde②:solvent is preferably 1:(3-20), and more preferably 1:(3-5).

[0028] In the step (1), the hydroxylamine is selected from hydroxylamine hydrochloride or a hydroxylamine aqueous solution.

[0029] In the step (1), the reaction time is preferably 2 to 11 hours, more preferably 6 to 8 hours; the reaction temperature is preferably 40 to 110°C, more preferably 70 to 90°C.

[0030] In the step (2), the nitrating agent is preferably nitric acid, fuming nitric acid, sulfuric acid and a mixture of one or more of nitrates, more preferably a nitric acid solution with a volume concentration of 65%.

[0031] In the step (2), the molar ratio of p-methoxybenzonitrile③ to the nitrating agent is 1:(1-5), more preferably 1:(1.1-1.3).

[0032] In the step (2), the reaction temperature of the nitration reaction is 30 to 90° C., more preferably 40 to 70° C.; the reaction time of the nitration reaction is preferably 5 to 11 hours, more preferably 7 to 8 hours.

[0033] In the step (3), the reducing agent is one of a mixture of a metal and ammonium chloride, hydrogen, hydrazine hydrate, and sodium dithionite. Preferably, it is a mixture of a metal and ammonium chloride, and more preferably, it is a mixture of zinc powder and ammonium chloride;

[0034] In the step (3), the molar ratio of 3-nitro-4-methoxybenzonitrile④: reducing agent is preferably 1:(1-10), more preferably 1:(3-5).

[0035] In the step (3), the molar ratio of 3-nitro-4-methoxybenzonitrile④:zinc powder:ammonium chloride is 1:(1-10):(1-10), more preferably 1:(3-5):(3-5).

[0036] In the step (3), the reduction reaction is carried out in a solvent, and the solvent used is preferably a mixture of one or more of methanol, ethanol, water, dichloromethane, tetrahydrofuran, benzene, and toluene, and more preferably water-ethanol. By volume ratio, 3-nitro-4-methoxybenzonitrile④:solvent is preferably 1:(3-20), more preferably 1:(4-8). Wherein by volume ratio, water:ethanol is 1:(1-3).

[0037] In the step (3), the reaction time is preferably 3 to 10 hours, more preferably 4 to 6 hours; the reaction temperature is preferably 20 to 90°C, more preferably 60 to 80°C.

[0038] In the step (4), the acylating agent is acetyl halide and / or acetic anhydride, more preferably acetic anhydride; in a molar ratio, 3-amino-4-methoxybenzonitrile ⑤: acylating agent = 1: (1 to 5), more preferably 1: (1.2 to 1.4).

[0039] In the step (4), the reaction is carried out in a reaction solvent, and the reaction solvent is preferably one or a mixture of methanol, ethanol, water, dichloromethane, tetrahydrofuran, benzene, toluene, and more preferably water. By volume ratio, 3-amino-4-methoxybenzonitrile ⑤: solvent is preferably 1: (1-20), more preferably 1: (3-5).

[0040] In the step (4), the reaction time is preferably 3 to 10 hours, more preferably 6 to 7 hours; the reaction temperature is preferably 20 to 70°C, more preferably 20 to 40°C.

[0041] In the step (5), the nitrating agent is one or a mixture of nitric acid, fuming nitric acid, sulfuric acid and nitrates, and the molar ratio of N-(5-cyano-2-methoxyphenyl)acetamide⑥ to the nitrating agent is 1:(1-2), more preferably 1:(1.1-1.6).

[0042] In the step (5), the reaction time is preferably 4 to 20 hours, more preferably 5 to 8 hours; the reaction temperature is preferably 0 to 100°C, more preferably 20 to 40°C.

[0043] A dacomitinib intermediate of the present invention is N-(4-amino-5-cyano-2-methoxyphenyl)acetamide, and its structural formula is:

[0044]

[0045] The method for preparing N-(4-amino-5-cyano-2-methoxyphenyl)acetamide, based on the method for preparing N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide ⑦, further comprises the following steps:

[0046] Step (6): reacting N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide⑦ with a reducing agent to generate N-(4-amino-5-cyano-2-methoxyphenyl)acetamide⑧;

[0047] In the step (6), the reducing agent is a mixture of a metal and ammonium chloride, hydrogen, hydrazine hydrate, or sodium dithionite. Preferably, it is a mixture of a metal and ammonium chloride, and more preferably, it is a mixture of zinc powder and ammonium chloride;

[0048] In the step (6), the molar ratio of N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide⑦:reducing agent is preferably 1:(1-10), more preferably 1:(3-5).

[0049] In terms of molar ratio, N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide⑦:zinc powder:ammonium chloride=1:(1-10):(1-10), more preferably 1:(3-5):(3-5).

[0050] In the step (6), the reaction is carried out in a reduction reaction solvent, and the reduction reaction solvent is preferably one or a mixture of methanol, ethanol, water, dichloromethane, tetrahydrofuran, benzene, toluene, and more preferably water-ethanol. By volume ratio, N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide⑦: solvent is preferably 1:(3-20), more preferably 1:(3-7). Wherein by volume ratio, water: ethanol is 1:(1-3).

[0051] In the step (6), the reaction time of the reduction reaction is preferably 4 to 20 hours, more preferably 9 to 12 hours; the reaction temperature of the reduction reaction is preferably 0 to 100° C., more preferably 40 to 70° C.

[0052] A dacomitinib intermediate of the present invention is N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide, and its structural formula is:

[0053]

[0054] The method for preparing the above-mentioned N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide, based on the method for preparing N-(4-amino-5-cyano-2-methoxyphenyl)acetamide⑧, further comprises the following steps:

[0055] Step (7): condensing N-(4-amino-5-cyano-2-methoxyphenyl)acetamide⑧ and N,N-dimethylformamide dimethyl acetal (DMF-DMA) to generate N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide⑨;

[0056] In the step (7), the molar ratio of N-(4-amino-5-cyano-2-methoxyphenyl)acetamide⑧:N,N-dimethylformamide dimethyl acetal (DMF-DMA) is 1:(1-3), more preferably 1:(1.2-1.5);

[0057] In the step (7), the condensation reaction is carried out in a solvent, and the solvent is preferably one or a mixture of toluene, xylene, tetrahydrofuran, dioxane, dimethyl sulfoxide, and more preferably toluene. By volume ratio, N-(4-amino-5-cyano-2-methoxyphenyl)acetamide⑧:solvent is 1:(1-20), and more preferably 1:(3-5).

[0058] In the step (7), the reaction time of the condensation reaction is preferably 4 to 24 hours, more preferably 9 to 12 hours; the temperature of the condensation reaction is preferably 40 to 110° C., more preferably 90 to 110° C.

[0059] A dacomitinib intermediate of the present invention is N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]acetamide, and its structural formula is:

[0060]

[0061] The method for preparing the above-mentioned N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]acetamide, based on the method for preparing N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide ⑨, further comprises the following steps:

[0062] Step (8): subjecting N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide ⑨ to a ring-closing reaction with 3-chloro-4-fluoroaniline to generate N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]acetamide ⑩;

[0063] In the step (8), the molar ratio of N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide ⑨:3-chloro-4-fluoroaniline is 1:(1-2), more preferably 1:(1.2-1.5).

[0064] In the step (8), the solvent for the ring-closing reaction is preferably one or more of methanol, ethanol, water, tetrahydrofuran, benzene, toluene, acetonitrile, and acetic acid, and more preferably acetic acid. By volume ratio, N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide ⑨: the solvent for the ring-closing reaction is preferably 1:(1-10), and more preferably 1:(3-5).

[0065] In the step (8), the reaction time of the ring-closure reaction is preferably 6 to 22 hours, more preferably 8 to 11 hours; the reaction temperature is preferably 10 to 120° C., more preferably 80 to 120° C.

[0066] A method for preparing dacomitinib of the present invention uses the above-mentioned dacomitinib intermediate, comprising the following steps:

[0067] Step (9): N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]acetamide ⑩ is hydrolyzed in an alkaline solution to generate N 4 -(3-Chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine ;

[0068] Step (10): Set N 4 -(3-Chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine , (E)-4-(piperidin-1-yl)-2-butenoyl chloride and an acid binding agent to generate dacomitinib①.

[0069] In the step (9), the alkaline hydrolysis process is to carry out alkaline hydrolysis in a sodium hydroxide solution and / or a potassium hydroxide solution; preferably sodium hydroxide; in a molar ratio, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]acetamide ⑩: sodium hydroxide = 1:(1-2), more preferably 1:(1.1-1.5).

[0070] In the step (9), the mass percentage concentration of the sodium hydroxide solution is 5%-30%, more preferably 10%.

[0071] In the step (9), the reaction time is preferably 6 to 21 hours, more preferably 8 to 10 hours; the reaction temperature is preferably 50 to 90°C, more preferably 80 to 90°C.

[0072] In the step (10), the acid binding agent is preferably one or a mixture of potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, more preferably N,N-diisopropylethylamine.

[0073] In the step (10), in molar ratio, N 4 -(3-Chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine : (E)-4-(piperidin-1-yl)-2-butenoyl chloride: acid binding agent = 1:(1.1-1.5):(1.1-3.0), more preferably 1:1.2:2.

[0074] In the step (10), the reaction time is preferably 2 to 10 hours, more preferably 2 to 4 hours; the reaction temperature is preferably -20 to 20°C, more preferably -15 to 0°C.

[0075] The reaction equations involved in the above steps are:

[0076]

[0077] A dacomitinib intermediate and dacomitinib and a preparation method thereof of the present invention have the beneficial effects of:

[0078] The present invention provides a preparation method of dacomitinib and a key intermediate thereof. Dacomitinib is synthesized by a novel preparation method, which comprises the following steps: using p-methoxybenzaldehyde② as a raw material, synthesizing N 4 -(3-Chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine , and then react with (E)-4-(piperidin-1-yl)-2-butenoyl chloride to synthesize dacomitinib①. In the process, the ring-closure reaction and the introduction of the fluorochloroaniline fragment are carried out in the same step, avoiding the use of highly polluting halogenated reagents. This is an efficient and environmentally friendly synthetic route suitable for industrial production. DETAILED DESCRIPTION

[0079] The present invention will be further described below with reference to the embodiments, but is not limited thereto.

[0080] Example 1: Preparation of p-methoxybenzonitrile ③

[0081] Dissolve 25g (183.62mmol) of p-methoxybenzaldehyde② in 75mL of formic acid and add it to a three-necked flask equipped with a thermometer, electromagnetic stirring and condenser, then add 16.59g (238.71mmol) of hydroxylamine hydrochloride. After the addition is completed, wait for the temperature to rise to 80℃, continue the reaction for 6h, and then stop the reaction. Add 200mL of ice water, filter and dry to obtain 22.68g of p-methoxybenzonitrile③, with a yield of 92.7%.

[0082] Example 2: Preparation of 3-nitro-4-methoxybenzonitrile ④

[0083] Add 40 mL of 65% nitric acid solution to a 100 mL three-necked flask, add 20 g (150.21 mmol) of p-methoxybenzonitrile ③ under stirring, heat to 45°C, react for 7 h, pour into ice water for crystallization, filter, dry, and recrystallize from anhydrous ethanol to obtain 24.65 g of light yellow solid 3-nitro-4-methoxybenzonitrile ④, with a yield of 92.5%.

[0084] Example 3: Preparation of 3-amino-4-methoxybenzonitrile ⑤

[0085] 20g (112.27mmol) 3-nitro-4-methoxybenzonitrile ④ was dissolved in 120mL anhydrous ethanol and added to a 500mL three-necked flask equipped with a thermometer, electromagnetic stirring and condenser, and 29.36g (449.07mmol) zinc powder, 24.02g (449.07mmol) ammonium chloride and 120mL water were added, and heated to 80°C for 4h. The saturated sodium bicarbonate solution was adjusted to pH 7-8, filtered, and the filtrate was extracted with dichloromethane (20mL×3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure to obtain 15.32g of white solid 3-amino-4-methoxybenzonitrile ⑤, with a yield of 92.6%.

[0086] Example 4: Preparation of N-(5-cyano-2-methoxyphenyl)acetamide ⑥

[0087] 20g (134.98mmol) 3-amino-4-methoxybenzonitrile⑤ and 100mL water were added to a 250mL eggplant-shaped bottle, and 16.7mL (175.48mmol) acetic anhydride was added dropwise. After the addition, the mixture was reacted at 25℃ for 6h. After suction filtration and natural drying, 23.72g of white solid N-(5-cyano-2-methoxyphenyl)acetamide⑥ was obtained, with a yield of 92.8%.

[0088] Example 5: Preparation of N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide⑦

[0089] Dissolve 15g (78.86mmol) of N-(5-cyano-2-methoxyphenyl)acetamide⑥ in 15mL of sulfuric acid and add to a 50mL three-necked flask equipped with a thermometer, electromagnetic stirring and condenser. Add a mixed acid solution containing 7.45g (118.3mmol) of nitric acid dropwise. After the addition, continue the reaction at 25℃ for 4h. Pour the mixed solution into ice water for crystallization. Filter and dry naturally to obtain 14.39g of yellow solid N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide⑦, with a yield of 77.6%, ESI-MSm / z: 236.1[M+H] + ,258.0[M+Na] + . 1 H NMR (600MHz, DMSO-d6) δ9.94(s,1H),8.75(s,1H),7.96(s,1H),4.07(s,3H),2.21(s,3H).

[0090] Example 6: Preparation of N-(4-amino-5-cyano-2-methoxyphenyl)acetamide⑧

[0091] Dissolve 15g (63.78mmol) of N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide⑦ in 80mL of anhydrous ethanol and add it to a 250mL three-necked flask equipped with a thermometer, electromagnetic stirring and condenser, and add 16.68g (255.10mmol) of zinc powder, 13.65g (255.10mmol) of ammonium chloride and 80mL of water. The temperature rises to 60℃ and the reaction is continued for 10h. Cool to room temperature, adjust the pH to 7-8 with saturated sodium bicarbonate solution, extract the filtrate with dichloromethane (15mL×3), wash the organic layer with saturated brine, dry with anhydrous sodium sulfate, and recover the solvent under reduced pressure to obtain 11.62g of white solid N-(4-amino-5-cyano-2-methoxyphenyl)acetamide⑧, with a yield of 90.3%, ESI-MS m / z: 228.09 [M+Na] + .

[0092] Example 7: Preparation of N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide ⑨

[0093] 20g (97.46mmol) of N-(4-amino-5-cyano-2-methoxyphenyl)acetamide⑧ was dissolved in 100mL of toluene and added to a 250mL three-necked flask equipped with a thermometer, electromagnetic stirring and condenser, and 15.10g (126.70mmol) of DMF-DMA and 1.11mL (19.49mmol) of glacial acetic acid were added. The temperature was raised to 110°C and the reaction was continued for 12h. The reaction was stopped and the solvent was recovered under reduced pressure to obtain 24.54g of yellow solid N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide⑨, with a yield of 96.6%, and ESI-MS m / z: 261.2 [M+H] + .

[0094] Example 8: Preparation of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]acetamide

[0095] 5g (19.21mmol) of N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide ⑨ was dissolved in 20mL of glacial acetic acid and added to a 50mL three-necked flask equipped with a thermometer, electromagnetic stirring and condenser, and 4.19g (28.81mmol) of 3-chloro-4-fluoroaniline was added. When the temperature rose to 120°C, the reaction was continued for 10h. After the reaction was completed, the solvent was evaporated to obtain 4.89g of white solid N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]acetamide ⑩, with a yield of 70.6%, and ESI-MS m / z: 361.18 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ9.77(s,1H),9.55(s,1H),8.79(s,1H),8.52(s,1H),8.12(dd,J=2.6, 6.8Hz,1H),7.83-7.75(m,1H),7.42(t,J=9.1Hz,1H),7.28(s,1H),4.01(s,3H),2.16(s,3H).

[0096] Example 9: N 4 -(3-Chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine Preparation

[0097] 10 g (13.86 mmol) of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]acetamide ⑩ and 50 mL of 10% NaOH aqueous solution were added to a 100 mL eggplant-shaped bottle, heated to 80°C, and the reaction was continued for 9 hours. After the reaction was complete, it was filtered to obtain a white solid N 4 -(3-Chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine 8.28 g, yield 93.8%, mp: 245-248°C, ESI-MS m / z: 319.1 [M+H]+.

[0098] Example 10: Preparation of Dacomitinib①

[0099] 5 g (15.69 mmol) N 4 -(3-Chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine After dissolving in 25 mL of tetrahydrofuran, add to a 100 mL three-necked flask, and add 4.05 g (31.37 mmol) of DIPEA. Add (E)-4-(piperidin-1-yl)-2-butenoyl chloride (3.53 g, 18.82 mmol) dropwise. After the addition, react at -15 ° C for 3 h. Stop the reaction, adjust the pH to 7-8 with 1 mol / L hydrochloric acid. Evaporate the solvent, extract with ethyl acetate (15 mL × 3), and wash the organic layer with saturated brine. Dry over anhydrous sodium sulfate, recover the solvent under reduced pressure, and recrystallize with 10 mL of isopropanol-water (2:1, v / v) to obtain 5.17 g of white solid dacomitinib ①, with a yield of 70.1%, ESI-MS m / z: 470.28 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ9.80(s,1H),9.68(s,1H),8.92(s,1H),8.54(s,1H),8. 13(dd,J=6.9,2.7Hz,1H),7.80(ddd,J=9.0,4.3,2.7Hz,1H),7.42(t,J=9.1Hz, 1H),7.29(s,1H),6.80(dt,J=15.4,6.0Hz,1H),6.56(d,J=15.4Hz,1H),4.01(s ,3H),3.10(d,J=6.9Hz,1H),2.38-2.35(m,4H),1.57-1.49(m,4H),1.40(m,2H). 13C-NMR(151MHz,DMSO-d6)δ163.97,157.13,155.72,154.31,154.20,152.70,142.42,137.20,127.61,126.13, 123.88,122.72,119.09,118.97,116.87,116.73,116.25,109.24,107.04,59.71,56.60,54.48,25.93,24.26.

[0100] The present invention adopts a series of new intermediates ⑦⑧⑨⑩ to synthesize dacomitinib ①, and the ring-closing reaction and the introduction of the fluorochloroaniline fragment are carried out in the same step. The use of toxic high-halogenated reagents such as thionyl chloride and phosphorus oxychloride is avoided, environmental pollution is reduced, and it is green and environmentally friendly.

[0101] The synthetic routes of the above embodiments 1 to 11 are:

[0102]

[0103] Embodiment 11

[0104] A method for preparing dacomitinib and the key intermediates involved, comprising the following process steps:

[0105] (1) p-Anisaldehyde② and hydroxylamine are reacted at 70° C. for 6 hours to prepare p-Anisaldehydenitrile③; the molar ratio of p-Anisaldehyde②:hydroxylamine is 1:1.1; compared with Example 1, the solvent used in this Example is ethanol.

[0106] (2) The p-methoxybenzonitrile ③ generated in step (1) is mixed with a nitrating agent, heated to 45° C., and subjected to a nitration reaction for 7 hours to generate 3-nitro-4-methoxybenzonitrile ④; the molar ratio of p-methoxybenzonitrile ③ to nitrating agent is 1:1.1; the nitrating agent used in this embodiment is potassium nitrate.

[0107] (3) reacting the 3-nitro-4-methoxybenzonitrile ④ generated in step (2) with a reducing agent at 70° C. for 5 hours to obtain 3-amino-4-methoxybenzonitrile ⑤; the reducing agent is sodium dithionite, and the molar ratio of 3-nitro-4-methoxybenzonitrile ④ to sodium dithionite is 1:4; the system is in a solvent, and the solvent used is toluene.

[0108] (4) reacting the 3-amino-4-methoxybenzonitrile ⑤ generated in step (3) with an acylating agent at 30° C. for 7 hours to generate N-(5-cyano-2-methoxyphenyl)acetamide ⑥; the acylating agent is an acetyl halide, and the molar ratio of 3-amino-4-methoxybenzonitrile ⑤ to the acylating agent is 1:1.3. The reaction solvent is dichloromethane.

[0109] (5) The N-(5-cyano-2-methoxyphenyl)acetamide ⑥ generated in step (4) is reacted with a nitrating agent at 30° C. for 8 hours to generate N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide ⑦; the nitrating agent used in this embodiment is potassium nitrate, and the molar ratio of N-(5-cyano-2-methoxyphenyl)acetamide ⑥ to nitrating agent is 1:2;

[0110] (6) reacting the N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide⑦ generated in step (5) with a reducing agent at 50°C for 10 hours to generate N-(4-amino-5-cyano-2-methoxyphenyl)acetamide⑧; the reducing agent used in this embodiment is a mixture of metallic zinc and ammonium chloride, with a molar ratio of metallic zinc:ammonium chloride = 1:1; and a molar ratio of N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide⑦:zinc powder:ammonium chloride = 1:4:4; the solvent used in this embodiment is methanol-water;

[0111] (7) reacting the N-(4-amino-5-cyano-2-methoxyphenyl)acetamide⑧ generated in step (6) with N,N-dimethylformamide dimethyl acetal (DMF-DMA) at 100° C. for 10 hours to generate N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide⑨; in a molar ratio, N-(4-amino-5-cyano-2-methoxyphenyl)acetamide⑧:N,N-dimethylformamide dimethyl acetal (DMF-DMA)=1:2; the solvent used in this embodiment is xylene;

[0112] (8) The N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide ⑨ produced in step (7) is reacted with 3-chloro-4-fluoroaniline at 80° C. for 10 hours to produce N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]acetamide ⑩; the molar ratio of N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide ⑨:3-chloro-4-fluoroaniline is 1:1.5; the reaction is carried out in a benzene solution.

[0113] (9) hydrolyzing the N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]acetamide (10) generated in step (8) under alkaline conditions to generate N 4 -(3-Chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine ; The molar ratio of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]acetamide⑩ to sodium hydroxide is 1:2.0; the mass concentration of sodium hydroxide used is 15%; the reaction temperature is 60°C and the reaction time is 12 hours;

[0114] (10) Substitute the N generated in step (9) 4 -(3-Chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine With (E)-4-(piperidin-1-yl)-2-butenoyl chloride, add acid-binding agent triethylamine, react at -5°C for 3 hours to generate dacomitinib①.

[0115] Among them, N 4 -(3-Chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine : The feeding molar ratio of (E)-4-(piperidin-1-yl)-2-butenoyl chloride:triethylamine is 1:1.2:2.0.

[0116] Example 12

[0117] A method for preparing dacomitinib comprises the following process steps:

[0118] (1) reacting p-methoxybenzaldehyde ② with hydroxylamine hydrochloride to prepare p-methoxybenzonitrile ③;

[0119] In this embodiment, the molar ratio of the raw material p-methoxybenzaldehyde② to hydroxylamine hydrochloride is 1:4;

[0120] The reaction is carried out in a solvent system, and the solvent is acetic acid.

[0121] The reaction time was 6 hours and the reaction temperature was 70°C.

[0122] (2) mixing the p-methoxybenzonitrile ③ generated in step (1) with a nitrating agent, heating to 45° C. to cause a nitration reaction to generate 3-nitro-4-methoxybenzonitrile ④;

[0123] In this embodiment, the nitrating agent is sulfuric acid with a volume concentration of 30%. The molar ratio of the raw material p-methoxybenzonitrile ③ to the nitrating agent is 1:1.1.

[0124] The reaction temperature was 40°C and the reaction time was 9 hours.

[0125] (3) reacting the 3-nitro-4-methoxybenzonitrile ④ generated in step (2) with a metal reducing agent to obtain 3-amino-4-methoxybenzonitrile ⑤;

[0126] In this embodiment, the reducing agent used is sodium dithionite, and the molar ratio of 3-nitro-4-methoxybenzonitrile④: sodium dithionite is 1:3;

[0127] The reaction is carried out in a reaction solvent, wherein the reaction solvent used in this embodiment is ethanol.

[0128] The reaction temperature was 60°C and the reaction time was 6 hours.

[0129] (4) reacting the 3-amino-4-methoxybenzonitrile ⑤ generated in step (3) with an acylating agent to generate N-(5-cyano-2-methoxyphenyl)acetamide ⑥;

[0130] The acylating agent used in this embodiment is acetic anhydride. The molar ratio of the raw material 3-amino-4-methoxybenzonitrile ⑤ to the acylating agent is 1:3.

[0131] The reaction is carried out in a reaction solvent, and the reaction solvent used in this embodiment is water.

[0132] The reaction temperature was 70°C and the reaction time was 3 hours.

[0133] (5) reacting the N-(5-cyano-2-methoxyphenyl)acetamide ⑥ generated in step (4) with a nitrating agent to generate N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide;

[0134] The nitrating agent used in this embodiment is a mixture of nitric acid and sulfuric acid, with a molar ratio of nitric acid: sulfuric acid = 1:1;

[0135] In this embodiment, the molar ratio of the raw material N-(5-cyano-2-methoxyphenyl)acetamide⑥: the nitrating agent for the nitration reaction is 1:1.6.

[0136] The nitration reaction temperature is 40° C., and the reaction time of the nitration reaction is 4 hours.

[0137] (6) reacting the N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide produced in step (5) with a reducing agent to produce N-(4-amino-5-cyano-2-methoxyphenyl)acetamide⑧;

[0138] In this embodiment, the reducing agent is sodium dithionite, and the molar ratio is N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide: sodium dithionite = 1:3;

[0139] In this embodiment, the solvent for the reduction reaction is toluene.

[0140] The reduction reaction temperature was 40° C., and the reduction reaction time was 20 hours.

[0141] (7) reacting the N-(4-amino-5-cyano-2-methoxyphenyl)acetamide⑧ generated in step (6) with N,N-dimethylformamide dimethyl acetal (DMF-DMA) to generate N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide⑨;

[0142] The solvent used in this embodiment is a mixed solvent of acetic acid and toluene in a volume ratio of 1:(1-3).

[0143] In terms of molar ratio, N-(4-amino-5-cyano-2-methoxyphenyl)acetamide⑧:N,N-dimethylformamide dimethyl acetal (DMF-DMA)=1:1.5.

[0144] In this embodiment, the reaction temperature is 110° C. and the reaction time is 4 hours.

[0145] (8) reacting the N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide ⑨ produced in step (7) with 3-chloro-4-fluoroaniline to produce N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]acetamide ⑩;

[0146] In this embodiment, the molar ratio of the raw materials N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide ⑨ to 3-chloro-4-fluoroaniline is 1:1.3.

[0147] In this embodiment, the solvent used is toluene.

[0148] The reaction temperature was 120°C and the reaction time was 6 hours.

[0149] (9) hydrolyzing the N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]acetamide (10) generated in step (8) under alkaline conditions to generate N 4 -(3-Chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine ;

[0150] In this embodiment, the alkaline hydrolysis condition is potassium hydroxide solution.

[0151] In this embodiment, the molar ratio of the raw materials N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]acetamide ⑩ to potassium hydroxide is 1:1.4.

[0152] In this embodiment, the mass percentage concentration of potassium hydroxide used is 20%.

[0153] The reaction temperature was 90°C and the reaction time was 6 hours.

[0154] (10) Substitute the N generated in step (9) 4 -(3-Chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine It is mixed with (E)-4-(piperidin-1-yl)-2-butenoyl chloride, and an acid-binding agent, potassium carbonate, is added to react to generate dacomitinib①.

[0155] Among them, the reaction raw material step (9) generates N 4 -(3-Chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine The molar ratio of (E)-4-(piperidin-1-yl)-2-butenoyl chloride and potassium carbonate is 1:1.5:3.0.

[0156] The above-mentioned implementation examples are only for illustrating the technical concept and features of the present invention. The purpose is to enable people familiar with this technology to understand the content of the present invention and implement it. It cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A dacomitinib intermediate, N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide, having the structural formula:

2. The method for preparing a dacomitinib intermediate according to claim 1, characterized in that: The preparation method of N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide specifically comprises the following steps: Step (1): mixing p-methoxybenzaldehyde and hydroxylamine hydrochloride to react to prepare p-methoxybenzonitrile; Step (2): mixing p-methoxybenzonitrile and a nitrating agent to carry out a nitration reaction to generate 3-nitro-4-methoxybenzonitrile; Step (3): subjecting 3-nitro-4-methoxybenzonitrile to a reduction reaction with zinc powder and ammonium chloride to obtain 3-amino-4-methoxybenzonitrile; Step (4): reacting 3-amino-4-methoxybenzonitrile with acetic anhydride to generate N-(5-cyano-2-methoxyphenyl)acetamide; Step (5): reacting N-(5-cyano-2-methoxyphenyl)acetamide with a nitrating agent to generate N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide.

3. A dacomitinib intermediate, N-(4-amino-5-cyano-2-methoxyphenyl)acetamide, having the structural formula:

4. A method for preparing a dacomitinib intermediate, characterized in that: The preparation method of N-(4-amino-5-cyano-2-methoxyphenyl)acetamide comprises the following steps: Step (6): react N-(5-cyano-2-methoxy-4-nitrophenyl)acetamide with zinc powder and ammonium chloride to generate N-(4-amino-5-cyano-2-methoxyphenyl)acetamide.

5. A dacomitinib intermediate, N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide, having the structural formula:

6. A method for preparing a dacomitinib intermediate, characterized in that: The preparation method of N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide comprises the following steps: Step (7): condensing N-(4-amino-5-cyano-2-methoxyphenyl)acetamide and N,N-dimethylformamide dimethyl acetal (DMF-DMA) to generate N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide; Wherein, in molar ratio, N-(4-amino-5-cyano-2-methoxyphenyl)acetamide:N,N-dimethylformamide dimethyl acetal (DMF-DMA)=1:(1-3); The condensation reaction is carried out in a solvent, which is one or a mixture of toluene, xylene, tetrahydrofuran, dioxane, and dimethyl sulfoxide; By volume ratio, N-(4-amino-5-cyano-2-methoxyphenyl)acetamide: solvent = 1: (1-20); The reaction time of the condensation reaction is 4 to 24 hours, and the temperature of the condensation reaction is 40 to 110°C.

7. A dacomitinib intermediate, which is N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]acetamide, having the structural formula:

8. A method for preparing a dacomitinib intermediate, characterized in that: The preparation method of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]acetamide comprises the following steps: Step (8): subjecting N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide to a ring-closing reaction with 3-chloro-4-fluoroaniline to generate N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]acetamide; Wherein, in molar ratio, N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide:3-chloro-4-fluoroaniline=1:(1-2); The solvent for the ring-closing reaction is one or more of methanol, ethanol, water, tetrahydrofuran, benzene, toluene, acetonitrile and acetic acid; By volume ratio, N-[5-cyano-4-[[(dimethylamino)methylene]amino]-2-methoxyphenyl]acetamide: solvent for ring-closure reaction = 1:(1-10); The reaction time of the ring-closure reaction is 6 to 22 hours, and the reaction temperature is 10 to 120°C.

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